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PubMed1982

In vivo microscopic studies of the responses of the liver to endotoxin.

In vivo microscopic methods concomitant with electron microscopic and histochemical procedures are being used to explore the sequelae of responses of Kupffer cells and the hepatic microvasculature to endotoxins. To gain further insight into the role of the liver in host defense and nonspecific resistance, the effects of endotoxin also are being studied in animals sensitized to endotoxin (BCG infection) or tolerant to endotoxin (pretreated with detoxified endotoxin, low doses of endotoxin, or in C3H/HeJ mice). The results to date, have demonstrated that endotoxin induces significant alterations in the hepatic microcirculation due to swelling of Kupffer and endothelial cells and the adhesion of leukocytes and platelets to the sinusoid wall. Lymphocytes frequently are associated with the Kupffer cells. Phagocytosis also is affected; following a brief period of stimulation, the rate of phagocytosis by Kupffer cells is depressed. In BCG infected animals all of these responses are exaggerated but can be minimized by pretreatment with detoxified endotoxin or minute concentrations of endotoxin 24 h prior to the challenge dose of endotoxin. The responses are not seen in the endotoxin low-responder, C3H/HeJ mouse which was found to have a deficiency in lysosomal enzymes and a paucity of functional Kupffer cells. The results provide some insight into the sequelae of cellular and microvascular events that occur in the liver during endotoxemia, endotoxin-related host defense mechanisms and non-specific resistance. In addition, support is provided for the central role of Kupffer cells in these events and that lysosomal enzymes participate in the toxic response elicited by endotoxin.

Animals↗

PubMed1991

Endotoxin-induced arachidonic acid metabolism requires de novo protein synthesis and protein kinase C activation.

The mechanisms whereby bacterial endotoxins stimulate arachidonic acid metabolism in macrophages are uncertain. Both protein kinase C activation and de novo protein synthesis occur in macrophages in response to endotoxin. In this study we evaluated the time course and role of protein kinase C and de novo protein synthesis in endotoxin stimulated arachidonic acid metabolism in resident rat peritoneal macrophages. Thromboxane (TX) B2 was measured as the representative arachidonic acid metabolite synthesized in response to Salmonella enteritidis endotoxin, calcium ionophore A23187, or phorbol 12-myristate 13-acetate (PMA). The effect of inhibition of protein kinase C by 1-(5-isoquinolinsulfonyl)-2-methylpiperazine dihydrochloride (H-7) and staurosporine on endotoxin- and A23187-induced TXB2 synthesis was examined. The potential roles of transcriptional and translational events in endotoxin- and A23187-stimulated TXB2 synthesis were determined by utilizing the transcriptional inhibitors camptothecin (10 microM) or actinomycin D (0.08 microM), and the translational inhibitor cycloheximide (0.1 microM). Whereas, A23187 stimulated maximal TXB2 synthesis within 15 min, endotoxin showed a more prolonged time course with a 12-fold increase in TXB2 synthesis above basal levels after 3 h (P less than 0.05). PMA induced an approx. 8-fold increase above basal TXB2 levels that was blocked by inhibition of transcription with actinomycin D. H-7 (10 microM to 50 microM) inhibited endotoxin- and A23187-stimulated eicosanoid synthesis. Staurosporine (0.2 microM) produced a selective 66% inhibition of endotoxin, but not A23187-stimulated TXB2 synthesis. Endotoxin-induced TXB2 production was significantly (P less than 0.05) inhibited by staurosporine, camptothecin, actinomycin D or cycloheximide at intervals from 30 min prior to, through 60 min after endotoxin stimulation. These studies suggest a role for protein kinase C activation and de novo protein synthesis in endotoxin signal transduction events leading to increased macrophage arachidonic acid metabolism. These intracellular events are essential in sustaining the prolonged inflammatory response to endotoxin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2002

Interleukin-10 reverses acute detrimental effects of endotoxin-induced inflammation on perinatal cerebral hypoxia-ischemia.

UNLABELLED: Perinatal brain injuries and the subsequent development of cerebral palsy are closely associated with intrauterine infections and inflammatory response. Antibiotics have proven futile in reducing perinatal brain injuries. We tested whether treatment with the anti-inflammatory cytokine IL-10 could have beneficial effects during a concomitant endotoxin and cerebral hypoxic-ischemic challenge. Thirty-three newborn piglets were randomized to pretreatment with: CONTROLS: placebo, Endotoxin: 2 kU/kg bolus and infusion of 1 kU/kg per h of endotoxin, or Endotoxin+IL-10: endotoxin in addition to 50 microg/kg of porcine recombinant IL-10. We induced cerebral hypoxia-ischemia by bilateral clamping of the common carotid arteries and ventilation with 8% oxygen for 20 min followed by 3 h of reoxygenation/reperfusion. Extracellular lactate, pyruvate, glycerol and glutamate, microcirculation and tissue oxygenation were monitored in the striatum by microdialysis, laser Doppler flow and oxygen tension probe, respectively. During and/or after cerebral hypoxia-ischemia, Endotoxin caused marked deterioration of the cerebral metabolic situation with higher lactate/pyruvate ratio (P=0.003), compared to CONTROLS and Endotoxin+IL-10. This was caused mainly by very low levels of pyruvate (P=0.001). During the following reoxygenation, Endotoxin compromised cerebral microcirculation (P=0.038) and tissue oxygenation (P=0.012) compared to CONTROLS and Endotoxin+IL-10. After a period of remission, a secondary energy failure and a new rise in the lactate/pyruvate ratio was seen in Endotoxin (P=0.002), but not in CONTROLS or Endotoxin+IL-10. At the end of observation, only the Endotoxin+IL-10 group had regained their baseline values in all variables. Thus IL-10 counteracts acute effects of endotoxin on cerebral metabolism, microcirculation and oxygen tension during hypoxia-ischemia in the perinatal brain.

Animals↗

PubMed2002

Endotoxins associated with cyanobacteria and their removal during drinking water treatment.

The aim of this study was to investigate endotoxin concentrations in cyanobacterial water blooms and strains, and to assess the removal of endotoxins during drinking water treatment. Endotoxin concentrations were measured from 151 hepatotoxic, neurotoxic and non-toxic cyanobacterial water blooms by using Limulus amebocyte lysate (LAL) assay, and the results were compared to bacterial data. Endotoxin activities ranged from 20 to 3.8 x 10(4) endotoxin units (EU) per ml. Endotoxicity of the samples correlated with phycobiliprotein concentration that was used to assess cyanobacterial abundance, heterotrophic plate count, and Aeromonas spp. but it did not correlate with the number of coliforms or streptococci. The high endotoxin concentrations occasionally detected in the water bloom samples were probably due to Gram negative bacteria that existed together with cyanobacteria since the 26 axenic cyanobacterial strains from different genera that were studied showed very low endotoxin activity. No differences in endotoxin activity were detected between hepatotoxic, neurotoxic and non-toxic strains. Removal of endotoxins during drinking water treatment was studied at nine waterworks that previously had been associated with high numbers of cyanobacteria and that used different processes for water purification. Endotoxin concentration in raw waters ranged from 18 to 356 EU ml(-1). The treatment processes reduced 59-97% of the endotoxin activity; in the treated water the concentration ranged from 3 to 15 EU ml(-1). The most significant reduction occurred at the early stages of water treatment, during coagulation, settling and sand filtration. Activated carbon filtration either increased or had no effect on endotoxin concentration. Ozonation and chlorination had little effect on the endotoxin concentrations.

Cyanobacteria↗

PubMed1997

Endotoxin as a factor in adverse reactions to latex gloves.

BACKGROUND: Endotoxin is an inflammatory made by gram negative bacteria that can irritate the skin, induce respiratory problems, fever, and shock. It is an adjuvant for both delayed hypersensitivity and IgE production and has been shown to magnify antigen specific mediator release. Since many of the clinical problems associated with natural latex products involve similar clinical sequelae, we investigated the possibility that latex gloves might be contaminated with endotoxin. OBJECTIVE: To measure the endotoxin content of a variety of natural latex gloves, investigate the its distribution and origin, associated with latex proteins, and determine the particle sizes associated with its release. METHODS: Endotoxin, protein, and allergen were measured using a quantitative kinetic Limulus assay, modified Lowry, and RAST inhibition, respectively. Particle size and density were determined using an Anderson multistage air sampler and CsCl2 gradient. RESULTS: Endotoxin was found to be a highly significant contaminant of some latex gloves. Levels ranged from 0.09 ng to 2.8 micrograms/g of glove. Protein levels ranged from < 25 to 1150 micrograms/g of glove while allergen levels ranged from < 1 to 837 micrograms/g of glove. Endotoxin and protein eluted rapidly from the interior of the gloves tested. Greater than 70% of the endotoxin was found to be associated with particles in the < 7 microns aerodynamic diameter range. The highest levels of endotoxin were found in nonsterile examination gloves with a tendency towards powdered gloves containing more endotoxin and protein. A slurry containing cross-linked dextran through which gloves were dipped revealed very high endotoxin contamination (64 micrograms/mL) while unused cross-linked dextran has very little associated endotoxin. CONCLUSIONS: These data demonstrate that some natural rubber latex gloves, particularly nonsterile examination gloves, are contaminated with high amounts of endotoxin and proteins. These were found mostly on the inside of gloves and were released as very small respirable particles that were not physically associated with the powder. These findings support the hypothesis that endotoxin may be responsible for some of the tissue irritation associated with latex glove use. In addition, this material may be responsible for the enhancement of delayed and immediate hypersensitivity reactions to chemicals and proteins found in these products and offers a possible explanation for the disproportionate severity of these reactions.

Allergens↗

PubMedDate not supplied

Endotoxin removal using a synthetic adsorbent of crystalline calcium silicate hydrate.

A synthetic adsorbent of crystalline calcium silicate hydrate, the product LRA by Advanced Minerals Corp., has been studied for endotoxin removal from aqueous solutions. This adsorbent removes endotoxin effectively, and the removal is greatly enhanced by the presence of an electrolyte such as NaCl, Tris-HCl, or Na2HPO4. It has an endotoxin removal capacity as high as 6 million endotoxin units (EU) per gram. Its endotoxin removal kinetics is fast, and for instance, over 99.9% endotoxin in a 5000 EU/mL solution was removed by mixing for 2 min at an adsorbent usage of 10 g/L. Using the chromatographic column method to treat a 5000 EU/mL solution, an endotoxin log-reduction factor of 6.2 was achieved with a single pass. This adsorbent also demonstrated significantly better performance when compared to many commonly used endotoxin removal agents, such as ActiClean Etox Endotoxin Removal Resin, Affi-Prep Polymyxin Support, Detroxi-Gel Endotoxin Removing Gel, Q Sepharose Fast Flow Media, and Sigma Endotoxin Removal Solution. Furthermore, it demonstrated a high selective removal of endotoxin from a solution of lambda DNA. This adsorbent provides opportunities for developing disposable, scaleable, and cost-effective methods for endotoxin reduction in many biotechnological and pharmaceutical processes.

Adsorption↗

PubMed2000

Determination of endotoxins in caries: association with pulpal pain.

AIM: The aims of this study were: (i) to determine the presence or absence of endotoxins in the superficial and deep layers of carious lesions of symptomatic and asymptomatic teeth with vital pulps; (ii) to quantify the amount of endotoxin present; and (iii) to associate the presence of endotoxins with the acute pulpal pain derived from the irreversible pulpitis. METHODOLOGY: Two specimens of carious dentine were taken under aseptic conditions from symptomatic teeth with irreversible pulpitis (n = 9) and asymptomatic teeth with reversible pulpitis (n = 11). The first specimen was taken from a layer of superficial caries and the second from a deeper one. Sound dentine was also collected from intact teeth without restoration and used as a noncarious control group (n = 4). During the patient sampling procedure an effort was made to collect an equal quantity of caries and sound dentine in all cases (approximately 6 mg). The extraction of endotoxins was performed using the Phenol-water method. The assay and quantitative determination of endotoxins was performed by the Quantitative Chromogenic test using Limulus Lysate. Data were analysed statistically using either independent or paired t-tests. RESULTS: The results indicated that endotoxins were present in the superficial and deep layers of caries of all symptomatic teeth with irreversible pulpitis (0.15078 and 0.12111 ng mL-1, respectively), with significantly greater amount (P < 0.01) in the superficial compared to the deep layer. Endotoxins were found in superficial and deep layer of caries of all asymptomatic teeth with reversible pulpitis (0.12091 and 0.07163 ng mL-1, respectively), with significantly greater amounts (P < 0.001) in the superficial compared to the deep layer. The results also demonstrated that significantly greater concentrations (P < 0.005) of endotoxins were present in the superficial carious layer of symptomatic compared with asymptomatic teeth (0.15078 and 0.12091 ng mL-1, respectively). Likewise, significantly greater amounts (P < 0.001) of endotoxins were present in the deep carious layer of symptomatic compared with asymptomatic teeth (0.12111 and 0.07163 ng mL-1, respectively). In sound dentine no endotoxins were detected. CONCLUSIONS: This study demonstrates that endotoxins are present in carious lesions of symptomatic and asymptomatic teeth. The amount of endotoxin was significantly greater in the superficial compared to the deep layer of carious dentine. More endotoxins are present in caries of painful teeth compared with those without symptoms.

Adolescent↗

PubMed1959

The effects of bacterial endotoxin on lipide metabolism. I. The responses of the serum lipides of rabbits to single and repeated injections of Shear's polysaccharide.

Single intravenous injections of Shear's polysaccharide in varying dosages invariably produced an elevation in the levels of the total serum lipides 24 hours after injection of endotoxin. The total serum cholesterol and lipide phosphorus were also affected, although they did not change with smaller doses of endotoxin and were rarely elevated to the same degree as were the total serum lipides. The degree of elevation of the serum lipides was apparently related to the amount of endotoxin injected up to a certain point, beyond which there was no further increase. There were two types of response to endotoxin by the serum lipides, a moderate increase and an uncontrolled increase. Higher dosages of endotoxin and fasting apparently increased the incidence of the latter response. No direct correlation could be made between serum lipide responses and histologic evidence typical of the generalized Shwartzman reaction following this regimen of endotoxin injection. The Shwartzman reaction did occur with greater frequency and with lower dosages of endotoxin in fasted animals. Animals given repeated injections of endotoxin showed an initial increase in serum lipides followed by a progressive decrease to normal levels as tolerance to the febrile action of endotoxin appeared. The febrile tolerance as well as the unresponsiveness of the serum lipides to endotoxin was abolished by thorium dioxide (thorotrast) in these animals. In similar experiments a "breakthrough" of lipide unresponsiveness to endotoxin was obtained by increasing the amount of endotoxin injected. Some of the implications of these results for the metabolic alterations produced by bacterial endotoxins are discussed.

Animals↗

PubMed2000

Endotoxin induces a dose-dependent myocardial cross-tolerance to ischemia-reperfusion injury.

OBJECTIVE: To test whether or not endotoxin induces a dose-dependent reduction of myocardial contractile dysfunction after a standardized period of myocardial ischemia and reperfusion and whether nitric oxide is involved in this form of myocardial protection. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Twenty-five male Sprague-Dawley rats. INTERVENTIONS: After anesthesia, the left carotid artery was cannulated under sterile conditions and animals were allowed to recover from surgery for 12 hrs. Sterile saline or increasing doses (2.5, 5, or 10 mg/kg body weight) of endotoxin (Escherichia coli O26:B6; Sigma, Mississauga, Ontario, Canada) were given intravenously (1 mL over 5 mins). In some rats, diaspirin-crosslinked hemoglobin (200 mg/kg) was infused 6 hrs and 60 min before endotoxin infusion (10 mg/kg). Hearts were rapidly excised for retrograde perfusion through the ascending aorta (Langendorff apparatus) 6 hrs later. After baseline data collection, hearts were subjected to global ischemia (30 mins, 37 degrees C [98.6 degrees F]), followed by 30 mins of reperfusion. MEASUREMENTS AND MAIN RESULTS: Physiologic variables were recorded 6 hrs after saline and endotoxin infusion. Baseline myocardial systolic contractility and diastolic compliance were assessed, respectively, by left ventricular developed pressure (LVDP) and left ventricular (LV) volume-preload relationships. After 30 min of reperfusion, LVDP recovery and left ventricular end-diastolic pressure were measured. Endotoxin induced LV systolic contractile depression, irrespective of the dose of endotoxin administered. LV diastolic dysfunction varied between different doses of endotoxin administered. On reperfusion, endotoxin produced a dose-dependent improvement of postischemic LVDP recovery: 30+/-6% in sham, 78+/-9% in 2.5 mg/kg, 93+/-8% in 5 mg/kg, and 107+/-10% in 10 mg/kg endotoxin heart. In rats treated with 10 mg/kg endotoxin, diaspirin-crosslinked hemoglobin pretreatment abrogated endotoxin-induced postischemic LVDP recovery improvement (105+/-10% vs. 43+/-7%, p = .01). CONCLUSION: Sublethal doses of endotoxin induce in a dose-dependent manner a delayed form of myocardial protection against ischemia. Although free-cell hemoglobin solution abrogates this endotoxin-induced cross-tolerance, we propose that possible mechanisms involved in this form of myocardial protection include nitric oxide pathway activation.

Animals↗

PubMed2005

Role of sensory neuron in reduction of endotoxin-induced hypotension in rats.

OBJECTIVE: We attempted to determine whether activation of the sensory neuron contributes to reduction of endotoxin-induced hypotension by inhibiting tumor necrosis factor (TNF)-alpha production via calcitonin gene-related peptide (CGRP) release in rats. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Wistar rats weighing 220-280 g. INTERVENTIONS: Mean arterial blood pressure was measured in rats administered endotoxin intravenously. Animals were pretreated with capsazepine (a vanilloid receptor antagonist), CGRP(8-37) (a CGRP receptor antagonist), and indomethacin before endotoxin administration. Levels of CGRP, 6-keto-prostaglandin F1alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant (CINC) were measured by enzyme immunoassay methods. The concentration of NO2/NO3 was measured using the Griess reagent. Tissue levels of messenger RNA of the inducible form of nitric oxide synthase (iNOS) and TNF-alpha were determined by reverse transcription polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Both lung levels of CGRP and plasma levels of 6-keto-prostaglandin F1alpha were increased after intravenous administration of endotoxin (5 mg/kg), peaking at 90 mins after endotoxin administration. Increases in plasma levels of 6-keto-prostaglandin F1alpha at 90 mins after endotoxin administration (766 +/- 134 pg/mL) were inhibited by pretreatment with capsazepine (373 +/- 44 pg/mL, p < .05), CGRP(8-37) (406 +/- 64 pg/mL, p < .05), and indomethacin (154 +/- 40 pg/mL, p < .05). Although none of the pretreatments affected a series of endotoxin-induced responses, including increases in lung tissue levels of TNF-alpha, CINC, and iNOS and the resultant hypotension in animals given 5 mg/kg endotoxin, such pretreatments enhanced these pathologic responses in animals given a smaller dose of endotoxin (1 mg/kg) to the same extent as those induced by 5 mg/kg of endotoxin, suggesting that shock responses induced by 5 mg/kg endotoxin are maximum responses and activation of sensory neurons in endotoxin-treated rats is essentially a reparative response. CONCLUSION: Activation of sensory neurons might contribute to reduction of endotoxin-induced hypotension by releasing CGRP, which is capable of promoting endothelial production of prostacyclin.

6-Ketoprostaglandin F1 alpha↗

PubMed2003

Endotoxin content in renal calculi.

PURPOSE: Manipulation of infection calculi (struvite and calcium apatite) can cause the sepsis syndrome due to endotoxemia or bacteremia. We sought to determine whether concentrations of endotoxin sufficient to produce the sepsis syndrome could be embedded in renal infection stones. MATERIALS AND METHODS: Fragments of infection and noninfection renal calculi were processed and assayed for endotoxin concentration. Endotoxin concentrations, recorded as endotoxin units per gm. calculus, were converted to ng. (10 endotoxin units = 1 ng.). Urine culture results were available for some patients with infection stones. RESULTS: A total of 34 renal calculi (16 infection and 18 noninfection) were evaluated. The composition of 62.5% of the infection stones was struvite, whereas 50% of the noninfection stones were calcium oxalate monohydrate. Mean endotoxin concentration in infection calculi was 12,223 ng./gm. stone (range 0.6 to 50,000), compared to 340.3 ng./gm. stone (range 0 to 3,490) in noninfection calculi. The endotoxin content difference was significant (p = 0.001). Urine culture results available from 9 patients with infection stones did not correlate with endotoxin concentrations. CONCLUSIONS: Large endotoxin concentrations can be found in renal infection calculi. Noninfection stones can contain endotoxin but in much lower amounts. Massive endotoxin release could occur with infection stone manipulation, possibly producing increased serum endotoxin concentrations similar to those seen in gram-negative sepsis. Anti-endotoxin strategies may be beneficial in preventing and treating stone induced endotoxemia and the sepsis syndrome.

Endotoxins↗

PubMed1988

Effects of urethane, ambient temperature and injection route on rat body temperature and metabolism due to endotoxins.

1. We have investigated the influence of environmental temperature, anaesthesia and route of administration on rectal temperature and other metabolic responses to two preparations of bacterial endotoxin in male adult Wistar rats. 2. Urethane anaesthesia, environmental temperatures of 20 and 28 degrees C, subcutaneous (S.C.) and intraperitoneal (I.P.) routes of administration and butanol and trichloroacetic acid (TCA) extracts of E. coli endotoxin (1.2 mg/kg) were used. 3. In addition to rectal temperature, serum zinc, albumin and urea concentrations and liver protein, RNA and zinc contents were measured. 4. Fevers were produced by injections of both endotoxins, by either route at 28 degrees C. Butanol-extracted endotoxin produced a more rapid response than the TCA extract via the I.P. route whereas the TCA extract produced a higher temperature than the butanol extract when the S.C. route was used. 5. Fevers were inhibited at an environmental temperature of 20 degrees C and by anaesthesia, while the former had no effect on compositional changes the latter inhibited the fall in serum zinc in response to subcutaneous doses of either endotoxin and the increase in liver zinc content in response to the butanol extract of endotoxin. 6. At 20 degrees C a marked fall in rectal temperature occurred in conscious rats 2 h after receiving the TCA but not the butanol extract of endotoxin. Temperature depression was more severe when endotoxin was administered by the I.P. route. 7. Serum urea was elevated in conscious rats by the TCA extract of endotoxin via both routes but only by the I.P. route for the butanol extract of endotoxin. In anaesthetized animals only the TCA extract of endotoxin raised serum urea concentration when given intraperitoneally. 8. Serum albumin and liver protein and RNA were unaffected by endotoxin injections over the 7 h time course of the study. 9. Rectal temperature responses to endotoxins were influenced in direction and magnitude by all variables employed in the study, while compositional changes were unaffected by environmental temperature but influenced to varying degrees by urethane anaesthesia and the route of administration employed.

Anesthesia↗

PubMed1991

Endotoxin-tobramycin additive toxicity on renal proximal tubular cells in culture.

Aminoglycoside-induced renal damage is enhanced in animals with Escherichia coli pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy. The toxic effect of endotoxin and tobramycin, alone or in combination, was investigated in primary cultures of rabbit proximal tubular cells grown to confluence in serum-free medium. Sodium-dependent uptakes of Pi and alpha-methylglucopyranoside (MGP) and enzymatic activities (lactate dehydrogenase [LDH] released as a marker of cell necrosis and gamma-glutamyltransferase [GGT] and N-acetyl-beta-D-glucosaminidase [NAG] present in the homogenate as markers of brush border membrane and lysosome integrity) were measured. Cells were exposed to (i) endotoxin (20 mg/liter), tobramycin (1 mM), or endotoxin plus tobramycin for 48 h, or (ii) endotoxin (100 mg/liter), tobramycin (4 mM), or endotoxin plus tobramycin for 72 h. Endotoxin alone did not alter Pi uptake, but tobramycin inhibited Pi uptake through a decrease in Vmax. The effect was not enhanced by the combination of endotoxin and tobramycin. Endotoxin and tobramycin alone exerted no significant effect upon MGP uptake, but strong inhibition of the Vmax was observed after exposure to a combination of endotoxin plus tobramycin, without alteration of the Km. Endotoxin decreased residual GGT activity in the cell homogenate. Tobramycin increased LDH release in the medium and NAG activity in the homogenate. Endotoxin plus tobramycin resulted in an additive effect upon LDH and NAG activities. In conclusion, by disturbing apical membrane integrity, endotoxin increased tobramycin toxicity in vitro in the absence of serum hormonal mediator.

Acetylglucosaminidase↗

PubMed1994

Endotoxin levels in sera of elderly individuals.

The endotoxin levels in serum of 377 72-year-old individuals were quantitated. The study population was a representative sample of this age group and was participating in a general study of health and disease among the elderly in Göteborg, Sweden. The endotoxin levels in serum were quantified by the chromogenic Limulus amebocyte lysate assay and were correlated with the health status and laboratory findings for each individual. The mean endotoxin levels (+/- 1 standard deviation) in men and women, when excluding four outliers, were 6.6 +/- 3.8 and 6.9 +/- 3.8 pg/ml, respectively. All included, 21.5% of individuals had endotoxin levels equal to or above the sensitivity limit of 10 pg/ml. Strong positive correlations were found between endotoxin levels and plasma triglycerides (P > 0.995) and between endotoxin levels and serum protein (P > 0.9875). The endotoxin activity also correlated with mean corpuscular hemoglobin concentration (P < 0.005, negative correlation), body mass index (P > 0.9875), and decreased appetite (P > 0.9875). A high alcohol consumption was associated with increased endotoxin levels (P = 0.995). There are no previous studies which examine endotoxin levels in serum samples from individuals representative of the population. This study showed that elderly individuals had the same mean level of endotoxin as has been found in other age groups. The increased endotoxin levels seen in heavy drinkers may be explained by a decreased ability of the liver to remove endotoxin. The correlations found between endotoxin and triglycerides, protein, mean corpuscular hemoglobin concentration, decreased appetite, and body mass index are discussed.

Aged↗

PubMed1986

Clearance of endotoxin from blood of rabbits injected with staphylococcal toxic shock syndrome toxin-1.

This study was undertaken to examine some of the properties of staphylococcal toxic shock syndrome toxin 1 (TSST-1) with regard to the clearance of endotoxin from blood. The concentration of endotoxin in blood was measured by using a chromogenic limulus test and modified perchloric acid method. When TSST-1, which produces fever in rabbits, was injected (100 ng/ml or 100 micrograms/ml per kg) intravenously (i.v.) into the animals, no measurable level of endotoxin was detected in the blood. In control animals, which were given 5 micrograms of endotoxin per ml per kg i.v., endotoxin could be detected in the blood at rapidly declining levels. These results suggested that TSST-1 might not lead bacterial endotoxin from other body sites into the blood. When the animals were given TSST-1 (1 to 100 ng/ml per kg) i.v. and then endotoxin (5 micrograms/ml per kg) i.v. 4 h later, endotoxin was detected in the blood at a high level, depending on the dose of TSST-1 injected. These results showed that TSST-1 inhibited the clearance of endotoxin in the blood; this clearance is thought to be mainly done by the reticuloendothelial system. In the animals given TSST-1 (100 ng/ml per kg) and endotoxin (5 micrograms/ml per kg) simultaneously, the endotoxin level in the blood was found to be higher than that in control animals given endotoxin only but lower than that in the animals given TSST-1 and then endotoxin at the same doses.

Animals↗

PubMed1989

Rat alveolar macrophage production of chemoattractants for neutrophils: response to Escherichia coli endotoxin.

Endotoxemia in rats is associated with the accumulation of neutrophils (polymorphonuclear leukocytes) within the airspaces of the lung. Polymorphonuclear leukocyte influx appears to be regulated by the intrapulmonary accumulation of chemotactic activity. Since alveolar macrophages (AMS) are prevalent cells in the airspace and are known to release a variety of chemotactic factors, we investigated the effect of endotoxin exposure on AM production of chemotactic activity. We tested the hypothesis that endotoxin-exposed AMs have an augmented ability to produce chemoattractants. We recovered AMs by bronchoalveolar lavage from control rats and from rats treated in vivo with a "low dose" (2.5 mg/kg) or a "high dose" (5.0 mg/kg) of Escherichia coli endotoxin. These AMs were then cultured in vitro for 15 h in the absence or the presence of endotoxin (15 and 30 micrograms/ml) to stimulate the cells to produce chemoattractants. We found that in vitro endotoxin stimulated normal AMs to secrete chemoattractants in a dose-dependent fashion. AMs from rats treated with endotoxin in vivo spontaneously secreted more chemoattractants than AMs from control rats. Exposure to in vivo endotoxin followed by in vitro stimulation with endotoxin resulted in an even greater production of chemoattractants by AMs. We found a significant association between the percent polymorphonuclear leukocytes recovered by bronchoalveolar lavage from the airspaces and the production of chemoattractants by AMs from the same specimen. The level of chemotactic activity spontaneously produced by AMs predicted the degree of stimulated production of chemotactic activity. Partial purification indicated that this chemotactic activity has two molecular weight peaks, one near 1,000 and the other near 50,000. The activity was stable at 100 degrees C for at least 30 min and was degradable by trypsinization. We conclude that endotoxin can induce AM production of chemoattractants and that prior exposure to endotoxin in vivo affects the response of AM to in vitro endotoxin exposure. By inference, it is possible that this endotoxin-macrophage interaction may serve as a biologic amplifier of the effects of endotoxin and may have a role in the pathogenesis of septic lung injury in humans.

Animals↗

PubMed1997

A1-adenosine receptor antagonists block endotoxin-induced lung injury.

Endotoxin produces a variety of biological effects on different cell types, such as priming of neutrophils and macrophages, which then release a number of important mediators of endotoxin-induced lung injury. However, the specific mechanism by which endotoxin initiates its cascade of pathophysiological events in the lung has not been described. Both A1 adenosine receptor activation and endotoxin induce the release of thromboxane A2 from the lung and inhibit adenylate cyclase. By acting on A1 adenosine receptors, adenosine promotes neutrophil chemotaxis and adherence to endothelial cells. We hypothesized that A1 adenosine receptor activation is essential to endotoxin-induced lung injury, and we used the highly selective A1-adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-benzyl-7,[2-[ethyl(2-hydroxyethyl)amino]-ethyl] theophylline (bamiphylline), to investigate whether selective blocking of the A1 adenosine receptor would prevent endotoxin-induced acute lung injury. An intralobar arterial infusion of endotoxin (15 mg/kg) into the left lower lobe of the lung in intact-chest, spontaneously breathing cats produced lung injury characterized by the presence of neutrophils, macrophages, and red blood cells (RBCs) in alveoli, and alveolar edema and necrosis. Lower doses of endotoxin (5 or 10 mg/kg) produced less severe and dose-dependent lung injury. Endotoxin (15 mg/kg)-induced alveolar injury was blocked in a highly significant manner by A1-adenosine receptor antagonists, DPCPX and bamiphylline. An intravenous bolus of DPCPX 30 min before endotoxin infusion or a continuous intravenous infusion of bamiphylline 30 min before, during, and 30 min after endotoxin reduced the percent injured alveoli (defined as the presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 57 +/- 31% (endotoxin 15 mg/kg) to 9 +/- 1% (DPCPX) or 21 +/- 14% (bamiphylline), which were not significantly different from control (1-h perfusion only) (4 +/- 1%) (P < 0.05). These data represent the first evidence that A1-adenosine receptor antagonism blocks the capacity of endotoxin to cause lung injury. A1-adenosine receptor antagonists may be useful in preventing adult respiratory distress syndrome associated with septicemia.

Animals↗

PubMed1996

Local venous responses to endotoxin in humans.

BACKGROUND: Septic shock is characterized by arterial and venous dilatation and decreased responsiveness to vasoconstrictors. We have developed a method to explore the effects and mechanisms of action of administration of endotoxin into a blood vessel in vivo. METHODS AND RESULTS: Endotoxin was instilled into a dorsal hand vein for 1 hour and then removed. A dose-response curve to norepinephrine was constructed before and 1, 2, 3, and 4 hours after endotoxin. In a separate study, dose-response curves to norepinephrine were constructed in two separate veins on the same hand, only one of which received endotoxin. Sympathetic-mediated venoconstrictor responses were also studied. Cyclooxygenase inhibitors, nitric oxide synthase inhibitors, and hydrocortisone were used to explore the mechanisms of the effects seen. Endotoxin caused a rightward shift in the dose-response curve to norepinephrine. The effect was greatest at 1 hour (maximal constriction: before endotoxin, 87 +/- 4%; after endotoxin, 52 +/- 8%; occlusion n = 4; P < .05) and returned to normal by 4 hours. In addition, deep-breath venoconstrictor responses were abolished in the endotoxin-treated vein. Instillation of endotoxin daily for 3 days resulted in the development of tolerance (maximal constriction to norepinephrine after endotoxin; day 1, 39 +/- 6%; day 2, 67 +/- 7%; day 3, 85 +/- 7%). Cyclooxygenase and/or nitric oxide synthase inhibitors did not alter the response to endotoxin, whereas prior administration of hydrocortisone abolished the effects. CONCLUSIONS: Instillation of endotoxin caused a glucocorticoid-inhibitable hyporesponsiveness to the constrictor effects of norepinephrine and abolished sympathetically induced and drug-induced venoconstriction. This acute response does not appear to be mediated by nitric oxide or prostanoids. Direct vascular tolerance to endotoxin occurs on repeated administration.

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